2015 — 2016 |
Chhatwal, Jasmeer P |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Age and Genetic Influence On Fcmri Networks in Autosomal Dominant and Sporadic Ad @ Massachusetts General Hospital
? DESCRIPTION (provided by applicant): This is a resubmitted application for a K23 Mentored Patient-Oriented Research Career Development Award. In terms of training, the applicant's goal is to utilize the K23 funding period to complete focused training in functional and image analysis, neuropathology, geriatrics, neuropsychology, and biostatistics. This training will take place through mentorship, a limited number of formal didactics, and through the completion of an ambitious project that will hopefully set the stage for future studies as an independent investigator. Functional connectivity MRI (fcMRI) is a non-invasive method to assess the integrity of anatomically distributed neural networks underlying complex behaviors. In Alzheimer's disease (AD), fcMRI of the default mode network (DMN) has shown great promise as a biomarker in clinical and basic research studies, as (1) profound decreases in DMN fcMRI are seen in prodromal and clinically evident AD and (2) the DMN is among the sites of early amyloid deposition in AD. However, using fcMRI as an early AD biomarker is limited by the overlapping changes in connectivity seen in normal aging, which, in turn, limits the identification of early AD subjects to enroll in clinical trials. To address this limitation, we propose a series f studies that use fcMRI to disambiguate normal aging from early AD by focusing on the pattern of degeneration across six well-described cortical networks in two unique subject populations. The central hypothesis of these studies is that early AD and aging will show distinct patterns of network degradation, with preferential degradation of cognitive networks (especially the Default Mode and Attention Networks) in early AD as compared to aging. We test this hypothesis by comparing young and old subjects with and without evidence of AD pathology, leveraging newly available data from young subjects with dominantly inherited AD (DIAD) drawn from the Dominantly-Inherited Alzheimer's Network (DIAN). Notably, the comparison of the DIAD population and older at-risk and symptomatic patients followed in the Harvard Aging Brain Study represents a unique opportunity to disentangle age and AD pathology, as DIAD carriers have disease onset at a young age (often in the late 30s and early 40s). In addition, using PET data on tau burden in our older subjects (from F18-T807 PET, a newly-developed tau radioligand), we will explore the relative contributions of amyloid and tau pathologies to altered fcMRI. These studies will serve the dual purpose of (1) optimizing the use of fcMRI as an AD biomarker by identifying patterns of fcMRI change that distinguish aging and AD, and (2) provide novel insight into the systems-level pathophysiology that distinguishes aging and AD. Further, these studies will compare the timing and pattern of network degradation in dominantly-inherited vs. sporadic AD and provide critical context for the interpretation of fcMRI data currently being gathered in (a least) three major AD prevention trials in older individuals at-risk for sporadic AD and dominantly-inherited AD.
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0.906 |
2017 — 2019 |
Chhatwal, Jasmeer P |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Age and Genetic Influence On Fcmri Networks in Autosomal Domit and Sporadic Ad @ Massachusetts General Hospital
? DESCRIPTION (provided by applicant): This is a resubmitted application for a K23 Mentored Patient-Oriented Research Career Development Award. In terms of training, the applicant's goal is to utilize the K23 funding period to complete focused training in functional and image analysis, neuropathology, geriatrics, neuropsychology, and biostatistics. This training will take place through mentorship, a limited number of formal didactics, and through the completion of an ambitious project that will hopefully set the stage for future studies as an independent investigator. Functional connectivity MRI (fcMRI) is a non-invasive method to assess the integrity of anatomically distributed neural networks underlying complex behaviors. In Alzheimer's disease (AD), fcMRI of the default mode network (DMN) has shown great promise as a biomarker in clinical and basic research studies, as (1) profound decreases in DMN fcMRI are seen in prodromal and clinically evident AD and (2) the DMN is among the sites of early amyloid deposition in AD. However, using fcMRI as an early AD biomarker is limited by the overlapping changes in connectivity seen in normal aging, which, in turn, limits the identification of early AD subjects to enroll in clinical trials. To address this limitation, we propose a series f studies that use fcMRI to disambiguate normal aging from early AD by focusing on the pattern of degeneration across six well-described cortical networks in two unique subject populations. The central hypothesis of these studies is that early AD and aging will show distinct patterns of network degradation, with preferential degradation of cognitive networks (especially the Default Mode and Attention Networks) in early AD as compared to aging. We test this hypothesis by comparing young and old subjects with and without evidence of AD pathology, leveraging newly available data from young subjects with dominantly inherited AD (DIAD) drawn from the Dominantly-Inherited Alzheimer's Network (DIAN). Notably, the comparison of the DIAD population and older at-risk and symptomatic patients followed in the Harvard Aging Brain Study represents a unique opportunity to disentangle age and AD pathology, as DIAD carriers have disease onset at a young age (often in the late 30s and early 40s). In addition, using PET data on tau burden in our older subjects (from F18-T807 PET, a newly-developed tau radioligand), we will explore the relative contributions of amyloid and tau pathologies to altered fcMRI. These studies will serve the dual purpose of (1) optimizing the use of fcMRI as an AD biomarker by identifying patterns of fcMRI change that distinguish aging and AD, and (2) provide novel insight into the systems-level pathophysiology that distinguishes aging and AD. Further, these studies will compare the timing and pattern of network degradation in dominantly-inherited vs. sporadic AD and provide critical context for the interpretation of fcMRI data currently being gathered in (a least) three major AD prevention trials in older individuals at-risk for sporadic AD and dominantly-inherited AD.
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0.906 |
2019 — 2021 |
Chhatwal, Jasmeer P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Linking Sleep Disruption to Tau Accumulation and Network Dysregulation in Early Alzheimer's Disease @ Massachusetts General Hospital
Project Summary/Abstract: Based on animal and limited human data, sleep disruption has been linked to decreased clearance and increased production of b-amyloid and tau, proteins which in their aggregated forms represent the two hallmark pathologies seen in Alzheimer?s disease. A number of different sleep parameters have also been closely tied to memory consolidation and chronic sleep disruption increases the risk of memory impairment in older individuals. However, despite data linking sleep disruption to Alzheimer?s disease pathology and memory impairment, significant gaps remain in our understanding of how sleep disruption evolves over the course of Mild Cognitive Impairment (MCI) and what aspects of sleep may be targets for intervention. In this context, we propose to directly examine the evolution of sleep disruption in relation to the in vivo progression of tau pathology, cognitive decline, and network dysfunction. Leveraging data that suggest that tau accumulation may be quite rapid during prodromal Alzheimer?s disease, we will focus these studies on individuals with MCI. We hypothesize that disrupted sleep architecture will be closely related to increased neocortical tau pathology and cognitive impairment, both cross-sectionally and longitudinally. Further, we hypothesize that sleep disruption leads to diminished connectivity in brain networks previously linked to memory performance and cognitive decline, and that this network dysregulation may partially mediate the effects of sleep disruption on cognition. Together, these studies will improve understanding on mechanistic links between sleep, cognition, and Alzheimer?s disease. More broadly, the data from these studies will critically inform the design of interventional studies modifying sleep in early Alzheimer?s disease by identifying which specific aspects of disrupted sleep are most closely tied to b-amyloid and tau pathology (potential therapeutic targets), assessing which aspects of sleep change over time in MCI, and the extent to which longitudinal polysomnography and actigraphy can measure aspects of sleep disruption relevant to Alzheimer?s disease.
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0.906 |
2020 |
Chhatwal, Jasmeer P |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Vascular Factors, Physical Activity, and Inflammation as Modulators of Neurodegenerative and Cognitive Trajectories (Project 2) @ Massachusetts General Hospital
SUMMARY: PROJECT 2- MODULATING FACTORS Disappointing results from recent trials targeting b-amyloid alone underscore it is critical that we identify, measure, and better understand factors outside of canonical Alzheimer?s pathology that influence the emergence of late-life cognitive decline. This need is particularly acute for potentially-modifiable risk factors for decline that can be targeted for intervention, either alone or in combination with therapies directed at b-amyloid or tau. In this context, this new project will leverage several core strengths of the Harvard Aging Brain Study (HABS) to assess the extent to which physical activity, inflammatory, and vascular factors modify longitudinal cognitive decline, MRI-based measures of neurodegeneration, and whether these potentially-modifiable risk factors interact with Alzheimer?s disease pathological cascades to cause accelerated neurodegeneration and cognitive decline. Aims 1 and 2: Building on cross-sectional and longitudinal PET, MRI, and cognitive data available in HABS, we will add objective, longitudinal assessments of vascular risk, white matter disruption due to putative cerebrovascular injury, and assessment of day and night activity patterns. Primary analyses for these aims will assess whether individual variations in vascular and activity parameters presage longitudinal changes in cognition (jointly with Project 4), changes in hippocampal volume, and in the accumulation of tau pathology as measured by PET (jointly with Project 1). Secondary analyses will assess regional variations in brain atrophy, examine the interplay of activity patterns with functional network integrity (jointly with Project 3), and identify cognitive domains which may be differentially impacted by these modulating factors. Together with the Analytic Core, we will employ causal models to examine the directionality of vascular and activity effects on cognitive and neurodegenerative trajectories and examine whether activity effects can be ascribed to reverse causation. Aim 3: In this exploratory aim, we will use a focused set of biofluid markers of vascular, inflammatory, and neurodegenerative processes to elucidate the mechanisms underlying the modulating factors we examine here. Together, these studies will allow us to develop a broader understanding of how these potentially-modifiable factors may interact with b-amyloid to modulate cognitive decline and neurodegeneration, and to go deeper by using newly-available, high-sensitivity immunoassays to identify biologic pathways underlying the effects of these potentially-modifiable risk factors.
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0.906 |
2021 |
Chhatwal, Jasmeer P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Plasma Tau and Neurodegenerative Markers as Predictors of Rate of Ad Progression @ Massachusetts General Hospital
Project Abstract: Alzheimer's disease and related dementias (ADRD) affect tens of millions of people around the world and represent a staggering challenge for patients, families, and healthcare systems. For some who present with mild levels of cognitive impairment, there is rapid worsening of cognition and function, whereas for others, the rate of progression can be absent or much slower. Understanding this variability in rate of progression is critically important to patients, families, and clinical researchers alike, and is not well-predicted by common, clinically available biomarker tools. Blood-based markers of AD pathology and neurodegeneration have potential for widespread use in clinical research and even clinical care, due to their non-invasiveness, cost relative to neuroimaging, and lack of medical contraindications to limit their use. Here we examine a set of newly developed, blood-based AD biomarkers (including neurofilament light chain, phospho-tau species, tau, and Ab fragments) that may fill this gap. Leveraging prospectively acquired samples from a large clinic population and from local clinical research studies, we will determine how these plasma measures relate to variable rates of real-world cognitive and functional decline, as well as to imaging-based measures of neurodegeneration and AD pathologic progression.
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0.906 |